A Bench-Stable Vilsmeier Reagent for in situ Alcohol Activation: Synthetic Application in the Synthesis of 2-Amino-2-Thiazolines

This paper is dedicated to Professor Vic Snieckus in honor of his 80^th birthday

Abstract

A robust, chemoselective direct condensation/cyclization of thioureas and amino alcohols is described. Employing a bench-stable Vilsmeier reagent, methoxymethylene-N,N-dimethyliminium methyl sulfate, the selective in situ activation of alcohols is achieved with high efficiency and broad functional-group tolerance. The reversible interaction of the Vilsmeier reagent with substrate was key to the success of this activation strategy.

Key words

alcohol activation - amino alcohols - chemoselectivity - condensation - thiazolines - thioureas - Vilsmeier reagents

• References and Notes

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• 21 At elevated reaction temperatures, the decomposition of 3 in the presence of NaOAc is a competing pathway leading to the generation of MeOAc. This deleterious pathway can be circumvented through the use of ⁱ Pr₂NEt. At ambient temperature, the background reaction of 3 and NaOAc is nonconsequential under the time scale of the reaction.
• 22 Representative Procedure for the Preparation of 2-Amino-2-thiazoline 6 To a stirred solution of ethanolamine 5a (1.35 mL, 22.4 mmol, 1.10 equiv) in DMF (40.0 mL, 0.5 M) at r.t. was added phenyl isothiocyanate 4a (2.40 mL, 20.0 mmol, 1.00 equiv). After stirring for 2 min at r.t., Vilsmeier salt 3 (7.20 g, 30.0 mmol, 1.50 equiv), and NaOAc (2.51 g, 30.6 mmol, 1.50 equiv) were added sequentially. The reaction mixture was allowed to stir at r.t. until adjudged complete by TLC, generally 4 h. The reaction was diluted with EtOAc (120 mL) and sequentially washed with sat. aq NaHCO₃ (40 mL) and brine (40 mL). The organic layer was dried over MgSO₄, polish filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (100% heptane to 80% EtOAc in heptane gradient) to give 6a (3.31 g, 18.6 mmol, 93% yield) as a white solid (mp 153 °C). Analytical Data for 6a ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.24 (m, 2 H), 7.16–7.08 (m, 2 H), 7.04–7.01 (m, 1 H), 6.36 (br s, 1 H), 3.78 (t, J = 7.04 Hz, 2 H), 3.27 (t, J = 7.04 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 161.83, 147.59, 128.89, 123.10, 121.12, 50.44, 31.81. ESI-HRMS: m/z calcd for C₉H₁₁N₂S [M + H]⁺: 179.06349; found: 179.06375. TLC (EtOAc/heptane, 1:1): R_f = 0.22. The spectral properties are in agreement with those previously reported in the literature.^6a
• 23 See Supporting Information for further information.
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